---

Autocoids: Amine-Derived, Peptide-Derived, and Lipid-Derived

---

I. AMINE-DERIVED AUTOCOIDS

1. Histamine

• Small doses: H1-mediated vasodilation → ↓BP, reflex tachycardia, flushing
• Large doses: H2-mediated direct cardiac stimulation

---

2. Serotonin (5-Hydroxytryptamine, 5-HT)

• Triptans (5-HT1B/1D agonists) - migraine
• SSRIs/SNRIs - depression/anxiety
• Ondansetron (5-HT3 antagonist) - chemotherapy-induced vomiting
• Metoclopramide, cisapride (5-HT4 agonists) - GI motility

---

II. PEPTIDE-DERIVED AUTOCOIDS

1. Bradykinin and the Kallikrein-Kinin System

Prekallikrein (activated by Factor XIIa) → Kallikrein → cleaves Kininogens → Kinins

• Plasma kallikrein cleaves HMW kininogen → Bradykinin (9 amino acids: Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg)
• Tissue kallikrein cleaves LMW kininogen → Kallidin (Lys-bradykinin, 10 amino acids), which can be converted to bradykinin by an aminopeptidase

• Kininase I (carboxypeptidase from liver) - cleaves C-terminal Arg
• Kininase II = ACE (Angiotensin Converting Enzyme) - cleaves the C-terminal dipeptide. This is why ACE inhibitors potentiate bradykinin - major contribution to their antihypertensive effect (and cause of ACE-inhibitor cough!)

• B2 receptor (constitutive) - mediates most physiological actions of bradykinin
• B1 receptor (inducible, upregulated in inflammation) - mediates pain and inflammatory responses

• Potent vasodilation (via NO and prostacyclin release from endothelium)
• Increased vascular permeability
• Bronchoconstriction
• Pain and hyperalgesia
• Stimulates prostaglandin synthesis
• Uterine and intestinal smooth muscle contraction

• ACE inhibitor-induced cough (due to bradykinin accumulation)
• Hereditary angioedema (C1-INH deficiency → uncontrolled kinin generation) - treated with icatibant (B2 antagonist), ecallantide (kallikrein inhibitor), or C1-INH concentrate

---

2. Natriuretic Peptides

---

3. Other Peptide Autocoids

• Substance P - neuropeptide (11 amino acids), released from sensory C-fibers; mediates pain transmission, neurogenic inflammation, vasodilation
• Angiotensin II - potent vasoconstrictor, aldosterone secretagogue (technically a hormone but acts locally too)
• Endothelins (ET-1, ET-2, ET-3) - produced by vascular endothelium; ET-1 is the most potent endogenous vasoconstrictor known; targeted by bosentan in pulmonary arterial hypertension

---

III. LIPID-DERIVED AUTOCOIDS (Eicosanoids + PAF)

Biosynthetic Pathways Overview

Membrane phospholipids
        |
   Phospholipase A2 (blocked by corticosteroids)
        |
  Arachidonic Acid
    /          \
COX pathway    LOX pathway    CYP pathway
(NSAIDs block)  (zileuton blocks)

---

A. COX Pathway Products (Prostanoids)

• Aspirin/NSAIDs - inhibit COX → analgesic, anti-inflammatory, antipyretic
• Misoprostol (PGE1 analog) - gastric cytoprotection, cervical ripening
• Dinoprostone (PGE2) - labor induction
• Latanoprost (PGF2α analog) - glaucoma
• Epoprostenol/iloprost (PGI2 analogs) - pulmonary arterial hypertension

---

B. LOX Pathway Products (Leukotrienes and Lipoxins)

• Montelukast, zafirlukast (CysLT1 receptor antagonists) - asthma, allergic rhinitis
• Zileuton (5-LOX inhibitor) - asthma
• Cysteinyl leukotrienes are the key mediators in aspirin-exacerbated respiratory disease (Samter's triad)

---

C. Platelet-Activating Factor (PAF)

• A phospholipid autocoid - 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine
• Produced by platelets, mast cells, neutrophils, monocytes, endothelium
• Acts on PAF receptor (PAFR) - a GPCR

• Platelet aggregation and activation
• Bronchoconstriction (potent)
• Vasoconstriction / vasodilation depending on concentration
• ↑Vascular permeability
• Chemotaxis and activation of leukocytes
• Key mediator in anaphylaxis and severe sepsis

---

Summary Table

---

• Katzung's Basic and Clinical Pharmacology, 16th Edition (Chapters 16, 17, 18)
• Goodman & Gilman's Pharmacological Basis of Therapeutics (Chapter 41 - Eicosanoids; Chapter 12)
• Ganong's Review of Medical Physiology, 26th Edition

---

---

AUTOCOIDS — Exam Question Bank

---

SECTION A: Single Best Answer (MCQs)

---

• A) Histaminase
• B) Histidine decarboxylase ✅
• C) Monoamine oxidase
• D) Diamine oxidase

Explanation: Histidine decarboxylase catalyzes the decarboxylation of L-histidine to histamine. MAO and diamine oxidase (DAO) are involved in its metabolism, not synthesis.

---

• A) Bradykinin
• B) Serotonin
• C) Histamine ✅
• D) Leukotriene C4

Explanation: IgE-mediated (Type I hypersensitivity) anaphylaxis is primarily driven by histamine released from mast cells and basophils. LTC4 contributes to bronchoconstriction but is secondary.

---

• A) On gastric parietal cells
• B) On presynaptic neurons in the CNS ✅
• C) On circulating eosinophils
• D) On vascular endothelium

Explanation: H3 receptors are presynaptic autoreceptors (and heteroreceptors) in the CNS and peripheral nerves. They inhibit release of histamine and other neurotransmitters (ACh, amines, peptides) via Gi → ↓cAMP.

---

• A) Diphenhydramine
• B) Promethazine
• C) Chlorpheniramine
• D) Fexofenadine ✅

Explanation: Fexofenadine is a second-generation H1 blocker that does not cross the blood-brain barrier significantly, hence minimal sedation. First-generation agents readily enter the CNS.

---

• A) N-methylserotonin
• B) 5-Hydroxyindoleacetic acid (5-HIAA) ✅
• C) Indoleacetic acid
• D) Homovanillic acid

Explanation: 5-HT is oxidized by MAO-A to 5-HIAA, which is excreted in urine. Elevated urinary 5-HIAA is a diagnostic marker for carcinoid tumors.

---

• A) 5-HT2A
• B) 5-HT3
• C) 5-HT1B/1D ✅
• D) 5-HT4

Explanation: Triptans are selective 5-HT1B/1D agonists. 5-HT1B receptors on cranial blood vessels cause vasoconstriction; 5-HT1D receptors on trigeminal nerve terminals inhibit neuropeptide release - both actions abort migraines.

---

• A) Renin
• B) Angiotensin-converting enzyme (ACE) ✅
• C) Chymase
• D) Tryptase

Explanation: Kininase II = ACE. It cleaves the C-terminal dipeptide from bradykinin, inactivating it. ACE inhibitors block this, prolonging bradykinin's action - contributing to their antihypertensive effect and causing the dry cough side effect.

---

• A) Angiotensin II
• B) Aldosterone
• C) Bradykinin ✅
• D) Substance P (direct)

Explanation: ACE inhibitors block kininase II, preventing bradykinin degradation. Accumulated bradykinin stimulates airway sensory C-fibres (which also release substance P and CGRP), causing cough. Switching to an ARB (which does not affect bradykinin) resolves the cough.

---

• A) Histamine and serotonin
• B) LTC4, LTD4, and LTE4 ✅
• C) PGD2 and TxA2
• D) PAF and bradykinin

Explanation: SRS-A, described before the individual components were identified, is the mixture of cysteinyl leukotrienes (LTC4, LTD4, LTE4). They cause sustained bronchoconstriction 100-1000x more potent than histamine.

---

• A) BLT1 (LTB4 receptor)
• B) DP2 (CRTH2)
• C) CysLT1 ✅
• D) EP4

Explanation: Montelukast and zafirlukast are CysLT1 receptor antagonists, blocking the action of LTC4, LTD4, and LTE4 on bronchial smooth muscle, reducing bronchoconstriction and mucus secretion.

---

• A) COX-2 only
• B) Phospholipase A2
• C) COX-1, preventing TxA2 synthesis ✅
• D) The thromboxane TP receptor

Explanation: Aspirin acetylates and irreversibly inhibits COX-1 in platelets (which lack nuclei and cannot synthesize new COX). This blocks TxA2 synthesis for the platelet's lifetime (~10 days). Vascular endothelial cells can regenerate COX-2 to produce PGI2.

---

• A) Leukocyte chemotaxis
• B) Platelet aggregation and vascular tone ✅
• C) Fever generation
• D) Uterine contractility

Explanation: PGI2 (from endothelium): vasodilation + inhibits platelets. TxA2 (from platelets): vasoconstriction + promotes platelet aggregation. The balance between these maintains vascular homeostasis.

---

• A) Misoprostol (PGE1)
• B) Latanoprost (PGF2α) ✅
• C) Epoprostenol (PGI2)
• D) Alprostadil (PGE1)

Explanation: Latanoprost is a PGF2α analog that reduces intraocular pressure by increasing uveoscleral outflow of aqueous humor. It is a first-line topical treatment for open-angle glaucoma.

---

• A) Directly blocking COX-2
• B) Inducing lipocortin (annexin A1) which inhibits phospholipase A2 ✅
• C) Inhibiting 5-lipoxygenase
• D) Blocking the thromboxane synthase enzyme

Explanation: Corticosteroids induce synthesis of lipocortin (annexin A1), which inhibits phospholipase A2 (PLA2). Since PLA2 liberates arachidonic acid from membrane phospholipids - the common precursor for all eicosanoids - all pathways (COX + LOX + CYP) are suppressed.

---

• A) Stimulating aldosterone release
• B) Activating guanylyl cyclase receptors → ↑cGMP ✅
• C) Inhibiting renin via Gi-coupled receptors
• D) Directly blocking ENaC channels

Explanation: ANP binds to particulate (membrane-bound) guanylyl cyclase receptors (GC-A/NPR-A), generating cGMP as second messenger, which causes vasodilation and natriuresis. It also inhibits renin and aldosterone release.

---

SECTION B: Extended Matching Questions (EMQs)

• A) Irreversible COX-1 inhibitor
• B) CysLT1 receptor antagonist
• C) 5-LOX inhibitor
• D) H2 receptor antagonist
• E) 5-HT3 receptor antagonist
• F) PGI2 analog
• G) H1 receptor antagonist (2nd generation)
• H) 5-HT1B/1D agonist
• I) Kallikrein inhibitor
• J) ETA/ETB receptor antagonist

---

SECTION C: Short Answer / High-Yield Vivas

---

---

1. Red line - local vasodilation (direct effect on capillaries)
2. Flare - surrounding erythema (axon reflex - sensory nerve stimulation)
3. Wheal - localized oedema (↑capillary permeability)

---

---

• Defect: C1-esterase inhibitor (C1-INH) deficiency (Type I) or dysfunction (Type II) → uncontrolled activation of plasma kallikrein → excess bradykinin generation → B2 receptor activation → massive ↑vascular permeability
• Acute treatment:
  • Icatibant - bradykinin B2 receptor antagonist
  • Ecallantide - plasma kallikrein inhibitor
  • C1-INH concentrate (Berinert, Cinryze) - replaces the deficient protein
• Prophylaxis: Lanadelumab (anti-kallikrein monoclonal antibody), C1-INH concentrate, tranexamic acid

---

• Inhibits platelet aggregation
• Causes vasodilation
• Is cardioprotective

---

• Structure: 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (acetylated phospholipid - NOT a classic eicosanoid)
• Sources: Platelets, mast cells, neutrophils, monocytes/macrophages, vascular endothelium
• Pathological roles:
  1. Anaphylaxis - potent bronchoconstriction and vasoconstriction
  2. Severe sepsis - hypotension via vasodilation at high concentrations, endothelial activation
  3. Asthma - bronchoconstriction + eosinophil recruitment; PAF-acetylhydrolase deficiency is linked to severe asthma in children

---

SECTION D: Fill in the Blanks (High-Yield Facts)

---

SECTION E: Scenario-Based (Integrated Thinking)

---

---

---

---

QUICK RECALL CARD

AMINE AUTOCOIDS
  Histamine: H1(Gq) H2(Gs) H3(Gi-presynaptic) H4(Gi-WBCs)
  Serotonin: 5-HT1(Gi) 5-HT2(Gq) 5-HT3(ion channel) 5-HT4(Gs)

PEPTIDE AUTOCOIDS
  Bradykinin: Kallikrein→Kininogens→BK; B1(inflam) B2(constitutive)
  ACE = Kininase II → inhibitors ↑BK → cough
  ANP/BNP: GC-A receptor → ↑cGMP → natriuresis
  ET-1: most potent vasoconstrictor; ECE synthesis; ETA(constrict) ETB(dilate)

LIPID AUTOCOIDS (all from AA via PLA2)
  COX → Prostanoids (NSAIDs/aspirin block)
    PGE2: fever, pain, vasodilation
    PGI2: vasodilation, ↓platelets (endothelium)
    TxA2: vasoconstriction, ↑platelets (platelets)
  LOX → Leukotrienes (zileuton blocks 5-LOX)
    LTB4: neutrophil chemotaxis
    LTC4/D4/E4: bronchoconstriction (montelukast blocks)
  PAF: platelet + mast cell product; anaphylaxis, sepsis

KEY DRUG LINKS
  Aspirin → irreversible COX-1 → antiplatelet
  Coxibs → ↓PGI2 only → ↑CV risk
  ACEi → ↑bradykinin → cough (not ARBs)
  Corticosteroids → lipocortin → ↓PLA2 → block all eicosanoids

---

---

AUTOCOIDS — Pharmacological Basis

In Correct Sequence: Amines → Peptides → Lipids

Definition: Autocoids (from Greek autos = self, akos = remedy) are endogenous substances synthesized and released locally, acting near their site of production. They differ from classical hormones (which travel in blood to distant organs) and neurotransmitters (which act across synapses). Together with cytokines, histamine, serotonin, peptides, prostaglandins, and leukotrienes constitute the autocoid group. - Katzung's Basic & Clinical Pharmacology, 16e

---

═══════════════════════════════

PART I: AMINE-DERIVED AUTOCOIDS

═══════════════════════════════

A. HISTAMINE

1. Chemistry & Synthesis

L-Histidine  →[Histidine decarboxylase]→  HISTAMINE

• N-methylation → N-methylhistamine (by histamine-N-methyltransferase)
• Oxidative deamination → Imidazoleacetic acid (IAA) (by MAO or DAO)
• Final metabolites excreted in urine

Clinical note: Systemic mastocytosis, urticaria pigmentosa, and gastric carcinoid are associated with excess mast cells and increased urinary histamine metabolites.

---

2. Release Triggers

• Immunological (IgE-mediated): Antigen cross-links IgE on mast cell surface → degranulation → Type I hypersensitivity
• Non-immunological: Drugs (morphine, tubocurarine, contrast media), physical stimuli (cold, pressure), complement fragments (C3a, C5a), neuropeptides

---

3. Receptors & Pharmacodynamics

H1 and H2 are postsynaptic in the brain; H3 is predominantly presynaptic.

---

4. Organ System Effects of Histamine

• Small doses (H1): vasodilation of arterioles/precapillary sphincters → ↓BP, reflex tachycardia, flushing
• Higher doses (H2): direct cardiac stimulation, ↑cAMP-mediated vasodilation
• Capillaries: H1-mediated ↑permeability → wheal & flare

• H1-mediated bronchoconstriction (especially in asthmatics)
• ↑Bronchial secretions

• H2-mediated ↑gastric acid & pepsin secretion from parietal cells
• H1-mediated ↑smooth muscle tone → cramps, diarrhoea

• H1: stimulates sensory nerve endings → pain and itch
• H3: modulates neurotransmitter release throughout CNS
• Pitolisant (H3 inverse agonist) → used in narcolepsy

1. Red line - direct capillary dilation
2. Flare - axon reflex (surrounding erythema)
3. Wheal - local oedema from ↑permeability

---

5. Pharmacological Antagonism of Histamine

First-generation H1 blockers also block muscarinic, α-adrenergic, and serotonin receptors - hence their antimuscarinic side effects (dry mouth, urinary retention, blurred vision) and sedation.

---

B. SEROTONIN (5-Hydroxytryptamine, 5-HT)

1. Chemistry & Synthesis

L-Tryptophan  →[Tryptophan hydroxylase ★ rate-limiting]→  5-HTP
5-HTP  →[Aromatic L-amino acid decarboxylase]→  SEROTONIN (5-HT)

• >90% in enterochromaffin cells of the GI tract
• Platelets (concentrated via SERT transporter; stored in vesicles by VAT, blocked by reserpine)
• CNS: raphe nuclei of brainstem (mood, sleep, appetite, pain, blood pressure, vomiting)

↑Urinary 5-HIAA is a key diagnostic marker for carcinoid tumour.

---

2. Receptors & Pharmacodynamics

---

3. Clinical Pharmacology

• Buspirone (5-HT1A partial agonist) → anxiolytic (non-benzodiazepine)
• Triptans - sumatriptan, zolmitriptan (5-HT1B/1D agonists) → migraine - cause cranial vasoconstriction + block trigeminal neuropeptide release

• Ondansetron, granisetron (5-HT3 antagonists) → chemotherapy-induced nausea/vomiting
• Cyproheptadine (H1 + 5-HT2 antagonist) → allergies, carcinoid syndrome
• Atypical antipsychotics (clozapine, olanzapine) → 5-HT2A blockade

• SSRIs (fluoxetine, sertraline) → inhibit SERT → ↑synaptic 5-HT → antidepressant, anxiolytic
• SNRIs (venlafaxine) → inhibit both SERT and noradrenaline transporter

---

═══════════════════════════════

PART II: PEPTIDE-DERIVED AUTOCOIDS

═══════════════════════════════

A. BRADYKININ & THE KALLIKREIN-KININ SYSTEM

1. Formation

Prekallikrein  →[Factor XIIa / FXIIa activates]→  KALLIKREIN
     ↓
PLASMA KALLIKREIN  →  cleaves HMW Kininogen  →  BRADYKININ (9 aa)
TISSUE KALLIKREIN  →  cleaves LMW Kininogen  →  KALLIDIN (Lys-bradykinin, 10 aa)
                                                        ↓ aminopeptidase
                                                   BRADYKININ

• Plasma kallikrein (activated by FXIIa): present in plasma; acts on HMW kininogen → bradykinin
• Tissue kallikrein (in kidney, pancreas, intestine, salivary glands, sweat glands): acts on LMW kininogen → kallidin

---

2. Metabolism of Kinins

• Kininase I (liver-derived carboxypeptidase N): cleaves C-terminal arginine
• Kininase II = ACE (Angiotensin Converting Enzyme): cleaves C-terminal dipeptide Phe-Arg — bradykinin is almost completely destroyed in ONE passage through the pulmonary circulation

This identity of Kininase II with ACE is pharmacologically pivotal: ACE inhibitors (enalapril, lisinopril) block bradykinin degradation → bradykinin accumulates → dry cough (B2 receptor activation of airway C-fibres → substance P release) and potentiation of antihypertensive effect.

---

3. Receptors & Actions

• Potent vasodilation (mediated by endothelial NO and prostacyclin)
• Pain and hyperalgesia (sensitises nociceptors)
• Stimulates prostaglandin synthesis - linking kinin and eicosanoid systems
• Bronchoconstriction and ↑mucus secretion
• Natriuresis and renal vasodilation

---

4. Clinical Pharmacology

---

B. NATRIURETIC PEPTIDES

---

C. ENDOTHELINS

• ET-1 (most abundant in blood vessels), ET-2, ET-3 - 21 amino acid peptides
• Synthesis: Preproendothelin → Big ET-1 → [Endothelin Converting Enzyme, ECE] → ET-1
• ET-1 is the most potent endogenous vasoconstrictor known

---

D. SUBSTANCE P

• Undecapeptide (11 amino acids); belongs to tachykinin family
• Released from primary afferent C-fibres and CNS neurons
• Receptor: NK1 (neurokinin-1), Gq-coupled
• Actions: pain transmission, neurogenic inflammation, vasodilation, emesis
• Aprepitant (NK1 antagonist) → chemotherapy-induced nausea/vomiting

---

═══════════════════════════════

PART III: LIPID-DERIVED AUTOCOIDS

═══════════════════════════════

Common Gateway: PLA2 → Arachidonic Acid

Membrane Phospholipids
         ↓ Phospholipase A2 (PLA2) [BLOCKED BY CORTICOSTEROIDS via lipocortin]
    Arachidonic Acid (AA)
    /              |              \
COX Pathway    LOX Pathway    CYP Pathway

---

A. COX PATHWAY → PROSTANOIDS

• COX-1 (constitutive): Expressed in virtually all cells; housekeeping - gastric mucosal protection, platelet TxA2, renal homeostasis
• COX-2 (inducible): Upregulated by cytokines, shear stress, growth factors; principal source of inflammatory prostanoids; also constitutive in kidney and brain

NSAIDs inhibit both COX-1 and COX-2. Coxibs (celecoxib, etoricoxib) selectively inhibit COX-2.

PGI2 vs TxA2 balance: PGI2 from endothelium opposes TxA2 from platelets. Selective COX-2 inhibitors (coxibs) suppress PGI2 without affecting platelet TxA2 → pro-thrombotic state → ↑cardiovascular risk (Vioxx withdrawal 2004).

---

B. LOX PATHWAY → LEUKOTRIENES & LIPOXINS

AA  →[5-LOX + FLAP]→  5-HPETE  →  LTA4 (unstable epoxide)
                                    /              \
                          LTA4 hydrolase      LTC4 synthase (+glutathione)
                                ↓                      ↓
                              LTB4              LTC4 → LTD4 → LTE4
                         (dihydroxy)          (cysteinyl leukotrienes)

The old term "Slow-Reacting Substance of Anaphylaxis" (SRS-A) refers to the mixture of LTC4, LTD4, and LTE4.

• Formed by interaction of 15-LOX and 5-LOX
• Act as "stop signals" for inflammation
• Inhibit neutrophil recruitment, promote resolution, counter-regulatory to leukotrienes
• Aspirin-triggered lipoxins also generated (aspirin-acetylated COX-2 produces 15R-HETE → 15-epi-LXA4)

---

C. CYP PATHWAY → EETs & HETEs

• Cytochrome P450 epoxidase → EETs (epoxyeicosatrienoic acids) → vasodilation, renal ion transport
• CYP ω-hydroxylase → 20-HETE → vasoconstriction, renal tubular Na⁺ regulation
• Less pharmacologically exploited than COX/LOX pathways currently

---

D. PLATELET-ACTIVATING FACTOR (PAF)

• Structure: 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (acetylated lysophospholipid)
• Sources: Platelets, mast cells, neutrophils, monocytes, vascular endothelium
• Receptor: PAF-R (PAFR) — GPCR (Gi/Gq)
• Metabolism: Rapidly inactivated by PAF-acetylhydrolase (PAF-AH)

• Platelet aggregation and activation at femtomolar concentrations
• Potent bronchoconstriction
• Vasoconstriction (low dose) / vasodilation (high dose)
• ↑Vascular permeability
• Leukocyte activation and chemotaxis
• Key mediator in anaphylaxis and severe sepsis/ARDS

---

MASTER INTEGRATION: How the Three Systems Interact

TISSUE INJURY / ANTIGEN
         |
    ┌────┴────────────────────────┐
    ↓                             ↓
MAST CELL DEGRANULATION      PLA2 ACTIVATION
    |                             |
HISTAMINE (amine)          ARACHIDONIC ACID
SEROTONIN (amine)              /      \
    |                      COX       LOX
    ↓                       |          |
Vasodilation              PGE2       LTB4 (chemotaxis)
Itch / pain               TxA2       LTC4/D4/E4 (bronchoconstriction)
↑Permeability             PGI2       Lipoxins (resolution)
    |
BRADYKININ (peptide)
- released by kallikrein
- amplifies vasodilation
- stimulates PG synthesis
- causes pain
- degraded by ACE

---

KEY PHARMACOLOGICAL PRINCIPLE — Common Inhibitor Hierarchy

---